Drugs companies active in the area of fertility control are always making efforts to improve the available contraceptives. Included therein is not only increasing the contraceptive reliability by developing novel substances and an improved convenience of use. On the contrary, innovative approaches to combining contraception and disease prevention are also being pursued.
A number of diseases is regarded as being connected with a folate deficiency. Thus, administration of folates for example in the form of folic acid may minimize the risk of cardiovascular disorders and certain malignant disorders (such as, for example, carcinoma of the breast or colon).
Defects in the development of unborn children are particularly serious consequences of folate deficiency in women of childbearing age. Thus, women with low folate levels have an increased risk, compared with those having sufficiently high folate levels, of giving birth to children suffering from congenital malformations such as neural tube, ventricular valve and urogenital defects.
Neural tube defects are the commonest congenital malformations of the central nervous system. They arise through incomplete closure of the neural tube in about the third to fourth week of embryonic development. Neural tube defects include spina bifida (in some cases with meningocele or meningomyelocele), encephalocele and anencephalies which are characterized by partial or complete absence of areas of the brain. Children with anencephaly are virtually incapable of survival.
Spina bifida is distinguished by incomplete closure of vertebral arches. Its result, depending on the nature of the lesion, is life-long disability in the form of various sensory but also motor deficits—thus, for example, two thirds of children and adults are dependent on wheelchairs owing to muscular paralyses. Therapy entails covering the defect, fitting a shunt to drain the CSF and lengthy orthopedic and neurological rehabilitation. The costs of the medical treatment average 500 000 € per child.
It is assumed that there are about 250 000 neonates with neural tube defects around the world. The rate of neonatal impairments in Germany and the USA is about 1-2 per 1000 births. In Germany each year about 500 babies are born alive with neural tube defects, while a further 500 pregnancies have been terminated on the basis of prenatal ultrasonic diagnosis.
Sufficiently high folate levels at the time of conception and in the initial phase of pregnancy are crucial for avoiding neural tube defects. An erythrocyte folate level of at least 906 nmol/l is generally regarded as desirable for reducing the frequency of neural tube defects.
It is known that intake of folic acid at the right time around conception can reduce neural tube defects by 50-70%. The folic acid fortification of food products which is practiced in the USA has already markedly reduced the incidence of neural tube defects; in Canada and Chile in fact by more than 50%.
Both voluntary fortification of food products as, for example, in Germany, and intake of folic acid products does not, however, reach all women of childbearing age to a sufficient extent. Firstly, many women are unaware of the risk of neural tube defects and the possibility of minimizing a corresponding risk by intake of folic acid. Thus, in many countries, far fewer than 10% of them take folic acid products around the time of conception. Secondly, despite modern methods of contraception, which are increasingly easy to use, a large number of pregnancies—estimated at up to 50% in the USA (Inst. of Medicine 1998, NEJM 2004)—are unplanned, so that deliberate intake of folic acid products before conception is likewise precluded from the outset. In addition, for example in the USA, about 5-8% of users do not take oral contraceptives reliably.
The object on which the U.S. Pat. No. 6,190,693 (Kafrissen et al.) was based was therefore to prevent certain disorders which can be treated by folic acid in consumers of oral contraceptives. Kafrissen achieved this object by adding folic acid to an oral contraceptive. He disclosed a method for administering folic acid by use of a pharmaceutical composition which comprised both conventional substances with contraceptive activity and folic acid.
However, introduction of folic acid into oral contraceptives itself involves a serious health risk, because it may mask the early symptoms, which are still treatable, of a vitamin B12 deficiency such as, for example, a megaloblastic anemia. This is because the hematological symptoms caused by vitamin B12 deficiency can be treated so well by additional folate administration that a vitamin B12 deficiency can be detected only with great difficulty, or not at all, and consequently therefore not diagnosed. The neuropsychiatric symptoms such as, for example, paresthesia and ataxia then remain untreated, however, and might deteriorate irreversibly.
The object on which the patent application WO 03/070255 (Coelingh Bennink) was based was therefore to avoid a health risk arising from the masking of the symptoms of a vitamin B12 deficiency in consumers of folic acid-containing oral contraceptives. Coelingh Bennink achieves this object by adding vitamin B12 to an oral contraceptive. He discloses a kit for oral hormonal contraception which comprises estrogens and/or progestogens, tetrahydrofolates and, obligatorily, vitamin B12.
A further problem associated with the administration of folic acid and tetrahydrofolate products—which comprise no 5-methyl-(6S)-tetrahydrofolate—is the polymorphism of methylenetetrahydrofolate reductase (MTHFR C677T), which is heterozygous in about 55% of the Caucasian population and homozygous in about 10-15%. This polymorphism leads to a reduced activity of methylenetetrahydrofolate reductase, so that the women affected are unable to metabolize sufficiently the supplied folate and tetrahydrofolate into 5-methyl-(6S)-tetrahydrofolate, which is active in the body. This polymorphism is an acknowledged risk factor for disorders caused by folate deficiency, in particular for neural tube defects.
A further problem causing difficulties is that folic acid is a substance which does not naturally occur in foodstuffs. In order to be biologically active, it must first be converted metabolically by the enzyme dihydrofolate reductase into 7,8-dihydrofolate and (6S)-tetrahydrofolate. The metabolic capacity, in particular the first activation step, for conversion of the provitamin folic acid into its active reduced form is limited and moreover varies greatly from individual to individual. Since the enzyme dihydrofolate reductase does not play a role in the metabolism of metafolin, interactions between medicaments which inhibit dihydrofolate reductase, such as, for example, methotrexate and dihydrofolate reductase are not to be expected.
In order to provide an adequate supply of folate also to women suffering from methylenetetrahydrofolate reductase deficiency, EP 0898965 (Müller et al.) proposes the use of 5-methyl-(6S)-tetrahydrofolic acid or appropriate pharmaceutically acceptable salts as dietary supplement or as ingredient of medicaments. EP 1044975 A1 discloses inter alia stable crystalline salts of 5-methyl-(6S)-tetrahydrofolic acid and processes for their preparation.
It is known that a large proportion of pregnancies occurs shortly after discontinuing the contraceptive (Farrow et al., Human Reproduction Vol. 17, No., 10, pp. 2754-2761, 2002). If administration is irregular and unreliable, pregnancy may even occur during intake. It is likewise known that even after termination of additional folate administration a person can profit therefrom for a further 90 days or so (FDA Advisory Committee for Reproductive Health Drugs (ACRHD): The public health issues, including the safety and potential clinical benefit, associated with combining folic acid and an oral contraceptive into a single combination product. Dec. 15, 2003; Summary Minutes, Question 4). However, it is a precondition for this that folic acid has been taken in sufficiently large amount in addition to the normal diet in a sufficiently long preceding period. This so-called tissue depot effect can be seen through elevated folate levels in the erythrocytes.
It is further known that low folate/high homocysteine levels are associated with multiple spontaneous abortions (Merlen et al., Obstet. et Gynecol. 2000, 95: pp. 519-524).
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.